Nutrition
Volume 26, Issue 5 , Pages 459-473 , May 2010

Obesity: Genes, brain, gut, and environment

  • Undurti N. Das, M.D., F.A.M.S.

      Affiliations

    • Corresponding Author InformationCorresponding author. Tel.: +216-231-5548; fax: +928-833-0316.

Received 24 March 2009 ,Accepted 27 September 2009.

References 

  1. Davis MM, McGonagle K, Schoeni RF, Stafford F. Grandparental and parental obesity influences on childhood overweight: implications for primary care practice. J Am Board Fam Med. 2008;21:549–554
  2. Eckel RH. Obesity and heart disease. Circulation. 1997;96:3248–3250
  3. Schultz LO, Schoeller DA. A compilation of total daily energy expenditures and body weights in healthy adults. Am J Clin Nutr. 1994;60:676–681
  4. Kimm SY, Glynn NW, Aston CE, Damcott CM, Poehlman ET, Daniels SR, et al. Racial differences in the relation between uncoupling protein genes and resting energy expenditure. Am J Clin Nutr. 2002;75:714–719
  5. Yanovski JA, Diament AL, Sovik KN, Nguyen TT, Li H, Sebring NG, et al. Associations between uncoupling protein 2, body composition, and resting energy expenditure in lean and obese African American, white, and Asian children. Am J Clin Nutr. 2000;71:1405–1420
  6. Kovacs P, Lehn-Stefan A, Stumvoll M, Bogardus C, Baier LJ. Genetic variation in the human winged helix/forkhead transcription factor gene FOXC2 in Pima Indians. Diabetes. 2003;52:1292–1295
  7. Ruige JB, Ballaux DP, Funahashi T, Mertens IL, Matsuzawa Y, Van Gaal LF. Resting metabolic rate is an important predictor of serum adiponectin concentrations: potential implications for obesity-related disorders. Am J Clin Nutr. 2005;82:21–25
  8. Krakoff J, Ma L, Kobes S, Knowler WC, Hanson RL, Bogardus C, et al. Lower metabolic rate in individuals heterozygous for either a frameshift or a functional missense MC4R variant. Diabetes. 2008;57:3267–3272
  9. Gomez-Ambrosi J, Catalan V, Diez-Caballero A, Martinez-Cruz LA, Gil MJ, Garcia-Foncillas J, et al. Gene expression profile of omental adipose tissue in human obesity. FASEB J. 2004;18:215–217
  10. Das UN. Perinatal nutriiton and obesity. Br J Nutr. 2008;99:1391–1392
  11. Das UN. Perinated supplementation of long-chain polyunsaturated fatty acids, immune response, and adult diseases. Med Sci Monit. 2004;10:19–25
  12. Das UN. Is metabolic syndrome X a disorder of the brain with the initiation of low-grade systemic inflammatory events during the perinatal period?. J Nutr Biochem. 2007;18:701–713
  13. Adam CL, Findlay PA, Chanet A, Aitken RP, Milne JS, Wallace JM. Expression of energy balance regulatory genes in the developing ovine fetal hypothalamus at midgestation and the influence of hyperglycemia. Am J Physiol Regul Integr Comp Physiol. 2008;294:R1895–R1900
  14. Das UN. A perinatal strategy for preventing adult disease: the role of long-chain polyunsaturated fatty acids. Boston: Kluwer Academic Publishers; 2002;
  15. Barker DJ, Hales CN, Fall CH, Osmond C, Phipps K, Clark PM. Type 2 (non-insulin dependent) diabetes mellitus, hypertension, and hyperlipidemia (syndrome X): relation to reduced fetal growth. Diabetologia. 1993;36:62–67
  16. Lucas A, Fewtrell MS, Cole TJ. Fetal origins of adult disease—the hypothesis revisited. BMJ. 1999;319:245–249
  17. Das UN. Is obesity an inflammatory condition?. Nutrition. 2001;17:953–966
  18. Gold RM, Quackenbush PM, Kapatos G. Obesity following combination of rostrolateral to VMH cut and contralateral mammillary area lesion. J Comp Physiol Psychol. 1972;79:210–218
  19. King BM, Smith RL, Frohman LA. Hyperinsulinemia in rats with ventromedial hypothalamic lesions: role of hyperphagia. Behav Neurosci. 1984;98:152–155
  20. Funahashi T, Shimomura I, Hiraoka H, Arai T, Takahashi M, Nakamura T, et al. Enhanced expression of rat obese (ob) gene in adipose tissues of ventromedial hypothalamus (VMH)-lesioned rats. Biochem Biophys Res Commun. 1995;211:469–475
  21. Paes AM, Carniatto SR, Francisco FA, Brito NA, Mathias PC. Acetylcholinesterase activity changes on visceral organs of VMH lesion-induced obese rats. Int J Neurosci. 2006;116:1295–1302
  22. Sakaguchi T, Bray GA, Eddlestone G. Sympathetic activity following paraventricular or ventromedial hypothalamic lesions in rats. Brain Res Bull. 1988;20:461–465
  23. Cox JE, Powley TL. Prior vagotomy blocks VMH obesity in pair-fed rats. Am J Physiol Endocrinol Metab. 1981;240:E573–E583
  24. Uno K, Katagiri H, Yamada T, Ishigaki Y, Ogihara T, Imai J, et al. Neuronal pathway from the liver modulates energy expenditure and systemic insulin sensitivity. Science. 2006;312:1656–1659
  25. Gautam D, Han SJ, Duttaroy A, Mears D, Hamdan FF, Li JH, et al. Role of the M3 muscarinic acetylcholine receptor in beta-cell function and glucose homeostasis. Diabetes Obes Metab. 2007;9(Suppl 2):158–169
  26. Edvell A, Lindstrom P. Vagotomy in young obese hyperglycemic mice: effects on syndrome development and islet proliferation. Am J Physiol Endocrinol Metab. 1998;274(6 Pt 1):E1034–E1039
  27. Kiba T, Tanaka K, Hoshino M, Misugi K, Inoue S. Ventromedial hypothalamic lesion-induced vagal hyperactivity stimulates rat pancreatic cell proliferation. Gastroenterology. 1996;110:885–893
  28. Imai J, Katagiri H, Yamada T, Ishigaki Y, Suzuki T, Kudo H, et al. Regulation of pancreatic β cell mass by neuronal signals from the liver. Science. 2008;322:1250–1254
  29. Thaler JP, Cummings DE. Food alert. Nature. 2008;452:941–942
  30. Wang PYT, Caspi L, Lam CKL, Chari M, Li X, Light PE, et al. Upper intestinal lipids trigger a gut-brain-liver axis to regulate glucose production. Nature. 2008;452:1012–1016
  31. Matzinger D, Degen L, Drewe J, Meuli J, Duebendorfer R, Ruckstuhl N, et al. The role of long chain fatty acids in regulating food intake and cholecystokinin release in humans. Gut. 2000;46:688–693
  32. Bado A, Levasseur S, Attoub S, Kermorgant S, Laigneau JP, Bortoluzzi MN, et al. The stomach is a source of leptin. Nature. 1998;394:790–793
  33. Barrachina MD, Martinez V, Wang L, Wei JT, Tache Y. Synergistic interaction between leptin and cholecystokinin to reduce short-term food intake in mice. Proc Natl Acad Sci U S A. 1997;94:10455–10460
  34. Fox EA, Murphy MC. Factors regulating vagal sensory development: potential role in obesities of developmental origin. Physiol Rev. 2008;94:90–104
  35. Komori T, Morikawa Y, Nanjo K, Senba E. Induction of brain-derived neurotrophic factor by leptin in the ventromedial hypothalamus. Neuroscience. 2006;139:1107–1115
  36. Hirano H, Day J, Fibiger HC. Serotonergic regulation of acetylcholine release in rat frontal cortex. J Neurochem. 1995;65:1139–1145
  37. Zhou FM, Liang Y, Dani JA. Endogenous nicotinic cholinergic activity regulates dopamine release in the striatum. Nat Neurosci. 2001;4:1224–1229
  38. Bartness TJ, Kay Song C, Shi H, Bowers RR, Foster MT. Brain-adipose tissue cross talk. Proc Nutr Soc. 2005;64:53–64
  39. Huang LZ, Winzer-Serhan UH. Nicotine regulates mRNA expression of feeding peptides in the arcuate nucleus in neonatal rat pups. Dev Neurobiol. 2007;67:363–377
  40. Obici S, Feng Z, Morgan K, Stein D, Karkanias G, Rossetti L. Central administration of oleic acid inhibits glucose production and food intake. Diabetes. 2002;51:271–275
  41. Obici S, Feng Z, Arduini A, Conti R, Rossetti L. Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production. Nat Med. 2003;9:756–761
  42. Lam TK, Pocai A, Gutierrez-Juarez R, Obici S, Bryan J, Aquilar-Bryan L, et al. Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nat Med. 2005;11:320–327
  43. Suresh Y, Das UN. Protective action of arachidonic acid against alloxan-induced cytotoxicity and diabetes mellitus. Prostaglandins Leukot Essent Fatty Acids. 2001;64:37–52
  44. Suresh Y, Das UN. Long-chain polyunsaturated fatty acids and chemically-induced diabetes mellitus: effect of ω-6 fatty acids. Nutrition. 2003;19:93–114
  45. Suresh Y, Das UN. Long-chain polyunsaturated fatty acids and chemically-induced diabetes mellitus: effect of ω-3 fatty acids. Nutrition. 2003;19:213–228
  46. Suresh Y, Das UN. Differential effect of saturated, monounsaturated, and polyunsaturated fatty acids on alloxan-induced diabetes mellitus. Prostaglandins Leukot Essent Fatty Acids. 2006;74:199–213
  47. Richard D, Guesdon B, Timofeeva E. The brain endocannabinoid system in the regulation of energy balance. Best Pract Res Clin Endocrinol Metab. 2009;23:17–32
  48. Di Marzo V. The endocannabinoid system in obesity and type 2 diabetes. Diabetologia. 2008;51:1356–1367
  49. Romanova IV, Ramos EJ, Xu Y, Quinn R, Chen C, George ZM, et al. Neurobiologic changes in the hypothalamus associated with weight loss after gastric bypass. J Am Coll Surg. 2004;199:887–895
  50. Xu Y, Ramos EJ, Middleton F, Romanova I, Quinn R, Chen C, et al. Gene expression profiles post Roux-en-Y gastric bypass. Surgery. 2004;136:246–252
  51. Tonra JR, Ono M, Liu X, Garcia K, Jackson C, Yancoupoulos GD, et al. Brain-derived neurotrophic factor improves blood glucose control and alleviates fasting hyperglycemia in C57BLKS-Lepr(db)/lepr(db) mice. Diabetes. 1999;48:588–594
  52. Ono M, Itakura Y, Nonomura T, Nakagawa T, Nakayama C, Taiji M, et al. Intermittent administration of brain-derived neurotrophic factor ameliorates glucose metabolism in obese diabetic mice. Metabolism. 2000;49:129–133
  53. Cao L, Lin E-JD, Cahill MC, Wang C, Liu X, During MJ. Molecular therapy of obesity and diabetes by a physiological autoregulatory approach. Nat Med. 2009;15:447–454
  54. Nonomura T, Tsuchida A, Ono-Kishino M, Nakagawa T, Taiji M, Noguchi H. Brain-derived neurotrophic factor regulates energy expenditure through the central nervous system in obese diabetic mice. Int J Exp Diabetes Res. 2001;2:201–209
  55. Suwa M, Kishimoto H, Nofuji Y, Nakano H, Sasaki H, Radak Z, et al. Serum brain-derived neurotrophic factor level is increased and associated with obesity in newly diagnosed female patients with type 2 diabetes mellitus. Metabolism. 2006;55:852–857
  56. Krabbe KS, Nielsen AR, Krogh-Madsen R, Plomgaard P, Rasmussen P, Erikstrup C, et al. Brain-derived neurotrophic factor (BDNF) and type 2 diabetes. Diabetologia. 2007;50:431–438
  57. Xu B, Goulding EH, Zang K, Cepoi D, Cone RD, Jones KR, et al. Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nat Neurosci. 2003;6:736–742
  58. Das UN. Is type 2 diabetes mellitus a disorder of the brain?. Nutrition. 2002;18:667–672
  59. Tran PV, Akana SF, Malkovska I, Dallman MF, Parada LF, Ingraham HA. Diminished hypothalamic bdnf expression and impaired VMH function are associated with reduced SF-1 gene dosage. J Comp Neurol. 2006;498:637–648
  60. Obici S, Feng Z, Tan J, Liu L, Karkanias G, Rossetti L. Central melanocortin receptors regulate insulin action. J Clin Invest. 2001;108:1079–1085
  61. Tamura H, Kamegai J, Shimizu T, Ishii S, Sugihara H, Oikawa S. Ghrelin stimulates GH but not food intake in arcuate nucleus ablated rats. Endocrinology. 2002;143:3268–3275
  62. Kamegai Tamura H, Shimizu T, Ishii S, Sugihara H, Wakabayashi I. Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and Agouti-related protein mRNA levels and body weight in rats. Diabetes. 2001;50:2438–2443
  63. Saad MF, Bernaba B, Hwu CM, Jinagouda S, Fahmi S, Kogosov E, et al. Insulin regulates plasma ghrelin concentration. J Clin Endocrinol Metab. 2002;87:3997–4000
  64. Broglio F, Gottero C, Van Koetsveld P, Prodam F, Destefanis S, Benso A, et al. Acetylcholine regulates ghrelin secretion in humans. J Clin Endocrinol Metab. 2004;89:2429–2433
  65. Dardennes RM, Zizzari P, Tolle V, Foulon C, Kipman A, Romo L, et al. Family trios analysis of common polymorphisms in the obestatin/ghrelin, BDNF and AGRP genes in patients with anorexia nervosa: association with subtype, body-mass index, severity and age of onset. Psychoneuroendocrinology. 2007;32:106–113
  66. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372:425–432
  67. Huang Q, Viale A, Picard F, Nahon J, Richard D. Effects of leptin on melanin-concentrating hormone expression in the brain of lean and obese Lep(ob)/Lep(ob) mice. Neuroendocrinology. 1999;69:145–153
  68. Das UN. Obesity, metabolic syndrome X, and inflammation. Nutrition. 2002;18:430–432
  69. Das UN. Aberrant expression of perilipins and 11-β-HSD-1 as molecular signatures of metabolic syndrome X in South East Asians. J Assoc Phys India. 2006;54:637–649
  70. Sinha S, Rathi M, Misra A, Kumar V, Kumar M, Jagannathan NR, et al. Subclinical inflammation and soleus muscle intramyocellular lipids in healthy Asian Indian males. Clin Endocrinol (Oxf). 2005;63:350–355
  71. Das UN. A perinatal strategy to prevent coronary heart disease. Nutrition. 2002;19:1022–1027
  72. Albert MA, Glynn RJ, Ridker PM. Plasma concentration of C-reactive protein and the calculated Framingham coronary heart disease risk score. Circulation. 2003;108:161–165
  73. van der Meer IM, de Maat MP, Hak AE, Kilian AJ, Del Sol AI, Van Der Kuip DA, et al. C-reactive protein predicts progression of atherosclerosis measured as various sites in the arterial tree. The Rotterdam study. Stroke. 2002;33:2750–2755
  74. Luc G, Bard J-M, Juhan-Vague I, Ferrieres J, Evans A, Amouyel P, et al. C-reactive protein, interleukins-6, and fibrinogen as predictors of coronary heart disease. The PRIME study. Arterioscler Thromb Vasc Biol. 2003;23:1255–1261
  75. Engstrom G, Hedblad B, Stavenow L, Lind P, Janzon L, Lindgarde F. Inflammation-sensitive plasma proteins are associated with future weight gain. Diabetes. 2003;52:2097–2101
  76. Barzilay JI, Abraham L, Heckbert SR, Cushman M, Kuller LH, Resnick HE, et al. The relation of markers of inflammation to the development of glucose disorders in the elderly. Diabetes. 2001;50:2384–2389
  77. Kim MJ, Yoo KH, Park HS, Chung SM, Jin CJ, Lee Y, et al. Plasma adiponectin and insulin resistance in Korean type 2 diabetes mellitus. Yonsei Med J. 2005;46:42–50
  78. Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events. Circulation. 2003;107:391–397
  79. Liu S, Manson JE, Buring JE, Stampfer MJ, Willett WC, Ridker PM. Relation between a diet with a high glycemic load and plasma concentrations of high-sensitivity C-reactive protein in middle-aged women. Am J Clin Nutr. 2002;75:492–498
  80. Pepys MB, Hirshfiled GM. C-reactive protein: a critical update. J Clin Invest. 2003;111:1805–1812
  81. Griselli M, Herbert J, Hutchinson WL, Taylor KM, Sohail M, Krausz T, et al. C-reactive protein and complement are important mediators of tissue damage in acute myocardial infarction. J Exp Med. 1999;190:1733–1739
  82. Gill R, Kemp JA, Sabin C, Pepys MB. Human C-reactive protein increases cerebral infarct size after middle cerebral artery occlusion in adult rats. J Cereb Blood Flow Metab. 2004;24:1214–1218
  83. Pepys MB, Hirschfield GM, Tennent GA, Gallimore JR, Kahan MC, Bellotti V, et al. Targeting C-reactive protein for the treatment of cardiovascular disease. Nature. 2006;440:1217–1221
  84. Esposito K, Nappo F, Marfella R, Giugliano G, Giugliano F, Ciotola M, et al. Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans. Role of oxidative stress. Circulation. 2002;106:2067–2072
  85. Kirwan JP, Krishnan RK, Weaver JA, Del Aguila LF, Evans WJ. Human aging is associated with altered TNF-α production during hyperglycemia and hyperinsulinemia. Am J Physiol Endocrinol Metab. 2001;281:E1137–E1143
  86. Lin Y, Rajala MW, Berger JP, Moller DE, Barzilai N, Scherer PE. Hyperglycemia-induced production of acute phase reactants in adipose tissue. J Biol Chem. 2001;276:42077–42083
  87. Cho HJ, Kim JK, Zhou XF, Rush RA. Increased brain-derived neurotrophic factor immunoreactivity in rat dorsal root ganglia and spinal cord following peripheral inflammation. Brain Res. 1997;764:269–272
  88. Oddiah D, Anand P, McMahon SB, Rattray M. Rapid increase of NGF, BDNF and NT-3 mRNAs in inflamed bladder. Neuroreport. 1998;9:1455–1458
  89. Virchow JC, Julius P, Lommatzsch M, Luttmann W, Renz H, Braun A. Neurotrophins are increased in bronchoalveolar lavage fluid after segmental allergen provocation. Am J Respir Crit Care Med. 1998;158:2002–2005
  90. Kerschensteiner M, Gallmeier E, Behrens L, Leal VV, Misgeld T, Klinkert WE, et al. Activated human T cells, B cells, and monocytes produce brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: a neuroprotective role of inflammation?. J Exp Med. 1999;189:865–870
  91. Tabakman R, Lecht S, Sephanova S, Arien-Zakay H, Lazarovici P. Interactions between the cells of the immune and nervous system: neurotrophins as neuroprotection mediators in CNS injury. Prog Brain Res. 2004;146:387–401
  92. Makar TK, Trisler D, Sura KT, Sultana S, Patel N, Bever CT. Brain derived neurotrophic factor treatment reduces inflammation and apoptosis in experimental allergic encephalomyelitis. J Neurol Sci. 2008;270:70–76
  93. Ricci A, Mariotta S, Saltini C, Falasca C, Giovagnoli MR, Mannino F, et al. Neurotrophin system activation in bronchoalveolar lavage fluid immune cells in pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2005;22:186–194
  94. Hahn C, Islamian AP, Renz H, Nockher WA. Airway epithelial cells produce neurotrophins and promote the survival of eosinophils during allergic airway inflammation. J Allergy Clin Immunol. 2006;117:787–794
  95. Bennedich Kahn L, Gustafsson LE, Olgart Hoglund C. Brain-derived neurotrophic factor enhances histamine-induced airway responses and changes levels of exhaled nitric oxide in guinea pigs in vivo. Eur J Pharmacol. 2008;595:78–83
  96. Lommatzsch M, Braun A, Mannsfeldt A, Botchkarev VA, Botchkarev NV, Paus R, et al. Abundant production of brain-derived neurotrophic factor by adult visceral epithelia. Am J Pathol. 1999;155:1183–1193
  97. Rost B, Hanf G, Ohnemus U, Otto-Knapp R, Groneberg DA, Kunkel G, et al. Monocytes of allergics and non-allergics produce, store and release the neurotrophins NGF, BDNF and NT-3. Regul Pept. 2005;124:19–25
  98. Noga O, Englmann C, Hanf G, Grutzkau A, Kunkel G. The production, storage and release of the neurotrophins nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 by human peripheral eosinophils in allergics and non-allergics. Clin Exp Allergy. 2003;33:649–654
  99. Rihl M, Kruithof E, Barthel C, De Keyser F, Veys EM, Zeidler H, et al. Involvement of neurotrophins and their receptors in spondyloarthritis synovitis: relation to inflammation and response to treatment. Ann Rheum Dis. 2005;64:1542–1549
  100. del Porto F, Aloe L, Lagana B, Triaca V, Nofroni I, D'Amelio R. Nerve growth factor and brain-derived neurotrophic factor levels in patients with rheumatoid arthritis treated with TNF-alpha blockers. Ann N Y Acad Sci. 2006;1069:438–443
  101. Grimsholm O, Guo Y, Ny T, Forsgren S. Expression patterns of neurotrophins and neurotrophin receptors in articular chondrocytes and inflammatory infiltrates in knee joint arthritis. Cells Tissues Organs. 2008;188:299–309
  102. Cai D, Holm JM, Duignan IJ, Zheng J, Xaymardan M, Chin A, et al. BDNF-mediated enhancement of inflammation and injury in the aging heart. Physiol Genomics. 2006;24:191–197
  103. Johansson M, Norrgard O, Forsgren S. Study of expression patterns and levels of neurotrophins and neurotrophin receptors in ulcerative colitis. Inflamm Bowel Dis. 2007;13:398–409
  104. di Mola FF, Friess H, Zhu ZW, Koliopanos A, Bley T, Di Sebastiano P, et al. Nerve growth factor and Trk high affinity receptor (TrkA) gene expression in inflammatory bowel disease. Gut. 2000;46:670–679
  105. Raap U, Werfel T, Goltz C, Deneka N, Langer K, Bruder M, et al. Circulating levels of brain-derived neurotrophic factor correlate with disease severity in the intrinsic type of atopic dermatitis. Allergy. 2006;61:1416–1418
  106. Bajzer M, Seeley RJ. Obesity and gut flora. Nature. 2006;444:1009–1010
  107. Backhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI. Host-bacterial mutualism in the human intestine. Science. 2005;307:1915–1920
  108. Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature. 2006;444:1022–1023
  109. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444:1027–1031
  110. Ley RE, Backhed F, Turnbaugh P, Lozupone CA, Knight RD, Gordon JL. Obesity alters gut microbial ecology. Proc Natl Acad Sci U S A. 2005;102:11070–11075
  111. Backhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A. 2004;101:15718–15723
  112. Backhed F, Manchester JK, Semenkovich CF, Gordon JI. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci U S A. 2007;104:979–984
  113. Varel VH, Pond WG, Pekas JC, Yen JT. Influence of high-fibre diet on bacterial populations in gastrointestinal tracts of obese- and lean-genotype pigs. Appl Environ Microbiol. 1982;44:107–112
  114. Samuel BS, Shaito A, Motoike T, Rey FE, Backhed F, Manchester JK, et al. Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty acid binding G protein-coupled receptor, Gpr41. Proc Natl Acad Sci U S A. 2008;105:16767–16772
  115. Amar J, Burcelin R, Ruiavets JB, Cani PD, Fauvel J, Alessi MC, et al. Energy intake is associated with endotoxemia in apparently healthy men. Am J Clin Nutr. 2008;87:1219–1223
  116. Zhang H, DiBaise JK, Zuccolo A, Kudrna D, Braidotti M, Yu Y, et al. Human gut microbiota in obesity and after gastric bypass. Proc Natl Acad Sci U S A. 2009;106:2365–2370
  117. Whitson BA, D'Cunha J, Hoang CD, Wu B, Ikramuddin S, Buchwald H, et al. Minimally invasive versus open Roux-en-Y gastric bypass: effect on immune effector cells. Surg Obes Relat Dis. 2009;5:181–193
  118. Das UN. Is metabolic syndrome X a disorder of the brain?. Curr Nutr Food Sci. 2008;4:73–108
  119. Middleton FA, Ramos EJB, Xu Y, Diab H, Zhao X, Das UN, et al. Application of genomic technologies: DNA microarrays and metabolic profiling of obesity in the hypothalamus and in subcutaneous fat. Nutrition. 2004;20:14–25
  120. Meguid M, Ramos EJB, Suzuki S, Xu Y, George ZM, Das UN, et al. A surgical rat model of human Roux-en-Y gastric bypass. J Gastrointest Surg. 2004;8:621–630
  121. Das UN. Metabolic syndrome X is a low-grade systemic inflammatory condition with its origins in the perinatal period. Curr Nutr Food Sci. 2007;3:277–295
  122. Das UN. Pathophysiology of metabolic syndrome X and its links to the perinatal period. Nutrition. 2005;21:762–773
  123. Bruning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC, et al. Role of brain insulin receptor in control of body weight and reproduction. Science. 2000;289:2122–2125
  124. Wu A, Ying Z, Gomez-Pinilla F. Dietary omega-3 fatty acids normalize BDNF levels, reduce oxidative damage, and counteract learning disability after traumatic brain injury in rats. J Neurotrauma. 2004;21:1457–1467
  125. Rao JS, Ertley RN, Lee HJ, DeMar JC, Arnold JT, Rapoport SI, et al. N-3 polyunsaturated fatty acid deprivation in rats decreases frontal cortex BDNF via a p38 MAPK-dependent mechanism. Mol Psychiatry. 2007;12:36–46
  126. Innis SM, de La Presa Owens S. Dietary fatty acid composition in pregnancy alters neurite membrane fatty acids and dopamine in newborn rat brain. J Nutr. 2001;131:118–122
  127. de La Presa Owens S, Innis SM. Diverse, region-specific effects of addition of arachidonic and docosahexaenoic acids to formula with low or adequate linoleic and alpha-linolenic acids on piglet brain monoaminergic neurotransmitters. Pediatr Res. 2000;48:125–130
  128. Peters JH, Simasko SM, Ritter RG. Modulation of vagal afferent excitation and reduction of food intake by leptin and cholecystokinin. Physiol Behav. 2006;89:477–485
  129. Ueno N, Dube MG, Inui A, Kalra PS, Kalra SP. Leptin modulates orexigenic effects of ghrelin and attenuates adiponectin and insulin levels and selectively the dark-phase feeding as revealed by central leptin gene therapy. Endocrinology. 2004;145:4176–4184
  130. Goto M, Arima H, Watanabe M, Hayashi M, Banno R, Sato I, et al. Ghrelin increases neuropeptide Y and agouti-related peptide gene expression in the arcuate Nucleus in rat hypothalamic organotypic cultures. Endocrinology. 2006;147:5102–5109
  131. Bassil AK, Dass NB, Sanger GJ. The prokinetic-like activity of ghrelin in rat isolated stomach is mediated via cholinergic and tachykininergic motor neurones. Eur J Pharmacol. 2006;544:146–152
  132. Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405:458–462
  133. Bernik TR, Friedman SG, Ochani M, DiRaimo R, Ulloa L, Yang H, et al. Pharmacological stimulation of the cholinergic antiinflammatory pathway. J Exp Med. 2002;195:781–788
  134. Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, et al. Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation. Nature. 2003;421:384–387
  135. Hersi AI, Kitaichi K, Srivastava LK, Gaudreau P, Quirion R. Dopamine D-5 receptor modulates hippocampal acetylcholine release. Brain Res Mol Brain Res. 2000;76:336–340
  136. Das UN. Alcohol consumption and risk of dementia. Lancet. 2002;360:490
  137. Minami M, Kimura S, Endo T, Hamaue N, Horafuji M, Togashi H, et al. Dietary docosahexaenoic acid increases cerebral acetylcholine levels and improves passive avoidance performance in stroke-prone spontaneously hypertensive rats. Pharmacol Biochem Behav. 1997;58:1123–1129
  138. Borkman M, Stolien LH, Pan DA, Jenkins AB, Chisholm DJ, Campbell LV. The relation between insulin sensitivity and the fatty acid composition of skeletal muscle phospholipids. N Engl J Med. 1993;328:238–244
  139. Das UN. A defect in the activity of Δ6 and Δ5 desaturases may be a factor predisposing to the development of insulin resistance syndrome. Prostaglandins Leukot Essent Fatty Acids. 2005;72:343–350
  140. Ginsberg BH, Jabour J, Spector AA. Effect of alterations in membrane lipid unsaturation on the properties of the insulin receptor of Ehrlich ascites cells. Biochim Biophys Acta. 1982;690:157–164
  141. Somova L, Moodley K, Channa ML, Nadar A. Dose-dependent effect of dietary fish-oil (n-3) polyunsaturated fatty acids on in vivo insulin sensitivity in rat. Methods Find Exp Clin Pharmacol. 1999;21:275–278
  142. Huang Y-J, Fang VS, Chou Y-C, Kwok C-F, Ho L- T. Amelioration of insulin resistance and hypertension in a fructose-fed rat model with fish oil supplementation. Metabolism. 1997;46:1252–1258
  143. Mori Y, Murakawa Y, Katoh S, Hata S, Yokoyama J, Tajima N, et al. Influence of highly purified eicosapentaenoic acid ethyl ester on insulin resistance in the Otsuka Long-Evans Tokushima fatty rat, a model of spontaneous non-insulin dependent diabetes mellitus. Metabolism. 1997;46:1458–1464
  144. Anthony K, Reed LJ, Dunn JT, Bingham E, Hopkins D, Marsden PK, et al. Attenuation of insulin-evoked responses in brain networks controlling appetite and reward in insulin resistance. The cerebral basis for impaired control of food intake in metabolic syndrome?. Diabetes. 2006;55:2986–2992
  145. Flores MBS, Fernandes MFA, Ropello ER, Faria MC, Ueno M, Velloso LA, et al. Exercise improves insulin and leptin sensitivity in hypothalamus of Wistar rats. Diabetes. 2006;55:2554–2561
  146. Spanswick D, Smith MA, Groppi VE, Logan SD, Ashford MLJ. Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels. Nature. 1997;390:521–525
  147. Harvey J, McKay NG, Walker KS, Van der Kay J, Downes CP, Ashford MLJ. Essential role of phosphoinositide 3-kinase in leptin-induced kATP channel activation in the rat CRI-GI insulinoma cell line. J Biol Chem. 2000;275:4660–4669
  148. Spanswick D, Smith MA, Mirshamsi S, Routh VH, Ashford MLJ. Insulin activates ATP-sensitive K+ channels in hypothalamic neuronsof lean, but not obese rats. Nat Neurosci. 2000;3:757–762
  149. Loftus TM, Jaworsky DE, Frehywot GL, Townsend CA, Ronnett GV, Lane MD, et al. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science. 2000;288:2379–2381
  150. McGarry GD, Mannaert GP, Foster DW. A possible role for malonyl-CoA in the regulation of hepatic fatty acid oxidation and ketogenesis. J Clin Invest. 1977;60:265–270
  151. Ruderman NB, Saha AK, Vavvas D, Witters LA. Malonyl-CoA fuel sensing and insulin resistance. Am J Physiol Endocrinol Metab. 1999;276:E1–18
  152. Ramos EJB, Suzuki S, Meguid MM, Laviano A, Sato T, Chen C, et al. Changes in hypothalamic neuropeptide Y and monoaminergic system in tumor-bearing rats: pre- and post-tumor resection and at death. Surgery. 2004;136:270–276
  153. Stranahan AM, Lee K, Martin B, Maudsley S, Golden E, Cutler RG, et al. Voluntary exercise and caloric restriction enhance hippocampal dendritic spine density and BDNF levels in diabetic mice. Hippocampus. 2009;19:951–961
  154. Ryan AS, Nicklas BJ. Reductions in plasma cytokine levels with weight loss improve insulin sensitivity in overweight and obese postmenopausal women. Diabetes Care. 2004;27:1699–1705
  155. Teixeira de Lemos E, Reis F, Baptista S, Pinto R, Sepodes B, Vala H, et al. Exercise training decreases proinflammatory profile in Zucker diabetic (type 2) fatty rats. Nutrition. 2009;25:330–339
  156. Das UN. Anti-inflammatory nature of exercise. Nutrition. 2004;20:323–326
  157. Shi X, Stevens GH, Foresman BH, Stern SA, Raven PB. Autonomic nervous system control of the heart: endurance exercise training. Med Sci Sports Exerc. 1995;27:1406–1413

 Dr. Das received a Ramalingaswami Fellowship from the Department of Biotechnology, India, during the tenure of this study.

PII: S0899-9007(09)00412-2

doi: 10.1016/j.nut.2009.09.020

Nutrition
Volume 26, Issue 5 , Pages 459-473 , May 2010